tbuckley/cabot-search huggingface dataset:
EXTH-79. HIJACKING A NEURODEVELOPMENTAL EPIGENOMIC PROGRAM IN METASTATIC DISSEMINATION OF MEDULLOBLASTOMA
Authors: Han Zou, Bradley Poore, Emily Brown, Patel Yash, Zhongliang Hu, Xuejun Li, Ian F Pollack, Robert M Friedlander, Sarah Hainer, Michael Taylor, Baoli Hu
Journal: Neuro-Oncology (2022)

Abstract Normal brain development relies on precise genetic and epigenetic spatiotemporal regulation of gene expression. How dysregulation of neurodevelopment relates to medulloblastoma, the most common pediatric brain tumor, remains elusive. Here, we uncovered a novel neurodevelopmental epigenomic program that regulates Purkinje cell migration in developing cerebellum is hijacked to induce tumor metastatic dissemination in medulloblastoma. Integrating publicly available datasets with our in-house data, unsupervised analyses revealed that BAF60C/SMARCD3, a subunit of SWI/SNF chromatin remodeling complex, promotes tumor cell migration in vitro and metastasis in vivo. Based on analyzing the single-cell RNAseq data of cerebellum developmental trajectory in mice and humans, aligning with the medulloblastoma patients’ datasets, we found that BAF60C/SMARCD3 regulated DAB1-mediated Reelin signaling is involved in Purkinje cell positioning during cerebellum development and medulloblastoma metastasis by orchestrating the cis-regulatory elements (CREs) at the DAB1 gene locus. Moreover, analysis of spatiotemporal gene expression and chromatin architecture in the human and mouse cerebellum demonstrated that transcription activity of the BAF60C/SMARCD3-DAB1 circuit is downregulated in a mature state of cerebellar development, however, is upregulated in metastatic medulloblastoma. We further identified that a core set of transcription factors, enhancer of zeste homolog 2 (EZH2) and nuclear factor I X (NFIX), bi-directionally control BAF60C/SMARCD3 transcriptional regulation by coordinating with the CREs at the BAF60C/SMARCD3 gene locus to form a chromatin hub during developing cerebellar development and medulloblastoma metastatic dissemination. Highly expressed BAF60C/SMARCD3 activates the Reelin/DAB1 signaling pathway downstream Src kinase, which was validated in the pair-wised primary and metastatic tumors from medulloblastoma patients. Preclinical medulloblastoma mouse models revealed that inhibiting Src activity reduces tumor cell migration and metastatic dissemination at a lower and safe dose. Together, these data deepen our understanding of how the developmental program influences disease progression and provide an opportunity for the development of therapeutics for this devastating brain cancer in children.
BIOM-17. SPYING ON GLIOMAS: LONGITUDINAL CSF AS A PLATFORM FOR GLIOMA MONITORING AND RESPONSE BIOMARKER DISCOVERY
Authors: Cecile Riviere-Cazaux, Samar Ikram, Siobhan Chantigian, Masum Rahman, Arthur Warrington, Terry Burns
Journal: Neuro-Oncology (2022)

Abstract The relative inaccessibility of a patient’s glioma throughout their disease course precludes individualized insights into tumor biology and responses thereof to therapeutic challenge. We propose that serial cerebrospinal fluid (CSF) samples can be used to perform glioma espionage in the form of biomarker discovery for analytes that are sensitive to tumor burden (for monitoring) and candidate therapies (for biological impact). To that end, we are routinely leveraging neurosurgical access to the CNS to collect CSF samples intraoperatively and from chronically implanted Ommaya reservoirs for longitudinal CSF access (NCT04692337, NCT04692324). Global proteomic analysis of CSF was performed on the Somalogic platform – an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Using each patient’s ranked protein list (glioma vs. 3 control patients), enrichment analysis was performed in a discovery cohort of five patients to identify conserved proteins of glioma. To reveal candidate glioma monitoring, further enrichment analysis was performed to identify proteins that decreased with resection and increased with recurrence, using two sets of paired patient samples. Forty-four proteins met these enrichment criteria; this candidate high-grade glioma proteomic signature was highly significantly enriched in an independent cohort of twelve glioma patients (FDR=0 for all patients). The HGG signature decreased in abundance following resection in serial samples from two other patients, confirming decreased tumor burden. Top proteins included LANC2, DPYL3, Sorcin, Integrin A1B1, and lactate dehydrogenase (FC of glioma vs. control: 145.3x, 113.9x, 78.0x, 71.6x, and 62.7x, respectively). Interestingly, despite having explicitly chosen samples with little-to-no hemoglobin in the discovery cohort, this HGG signature was highly enriched for plasma-like proteins (FDR=0), suggesting a potential biological impact of blood-brain barrier disruption on the glioma extracellular proteome. In conclusion, our data demonstrate that the glioma extracellular proteome can feasibly be accessed to perform biomarker discovery (“espionage”) via serially-acquired CSF samples.
CTIM-02. TIP: PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES
Authors: Colette Shen, Yara Abdou, Xianming Tan, Gaorav Gupta, Filipa Lynce, Erica Stringer-Reasor, Carey Anders
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis (BrM) for HER2+ breast cancer (BC), outcomes for patients with HER2-negative BC BrM remain poor. Current standard of care consists of local therapies, including surgery and radiotherapy, followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective with radiation therapy as a DNA damage response inhibitor. Triple negative BC (TNBC) has higher rates of homologous recombination deficiency compared to other BC subtypes, and together with HER2-negative, BRCA-mutated BC would be particularly sensitive to PARP inhibition. PARP inhibition also shows promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with BrM. We hypothesize that this biologically-rational combination will enhance local control of SRS-treated BrM through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites via potentiation of the immune response. METHOD We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) BC BrM [NCT04711824]. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II) of this treatment combination. Secondary objectives include determining clinical activity via intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study will evaluate olaparib concentration/distribution in resected BrM.
SURG-06. PREOPERATIVE NEOADJUVANT GAMMA KNIFE RADIOSURGERY IN THE TREATMENT OF LARGE BRAIN METASTASIS: AN INITIAL CASE SERIES OF SINGLE INSTITUTE
Authors: Seon-Hwan Kim, Kyung Hwan Kim, Han-Joo Lee, Hyon-Jo Kwon, Seung-Won Choi, Hyeon-Song Koh, Jin-Young Youm
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Postoperative stereotactic radiosurgery (SRS) following the surgical resection of large brain metastasis is a promising therapeutic option to reduce local recurrence. However, there is an increased risk of radiation necrosis and leptomeningeal spreading and an issue of problematic target delineation. Neoadjuvant SRS, also called preoperative SRS, is an emerging treatment paradigm which delivers radiation in the preoperative setting. An initial series of single-institute cases treated with the neoadjuvant SRS followed by surgical resection of a large BM was reviewed. Method: Between 2019 and 2022, 5 patients underwent neoadjuvant SRS using Gamma Knife radiosurgery (GKS) unit, followed by surgical resection. Local tumor recurrence, distant tumor recurrence, leptomeningeal seeding, and overall survival were investigated. Pathologic findings and surgical gross findings were reviewed. RESULTS The mean age was 59 and 3 patients were female. All patients had multiple lesions, ranged 2 to 7, including a large lesion (mean tumor volume: 29.8 cc). The interval between GKS and surgery was varied between 1 to 14 days. The prescribed dose of plan-to-resect lesion was 12 Gy in four patients and 14 Gy in one patient. All patients underwent gross total resection without surgical complications and had no radiation-induced toxicity. 3 patients were died of extracranial progression during follow-up period, including 1 patient who died before the first follow-up image. Local tumor progression was noted in 1 patient 9 months after treatment. The mean overall survival was 4.5 months although two patients continued to require follow-up. CONCLUSIONS Neoadjuvant SRS may be safe and advantageous for the treatment of BM that require surgical intervention. Long-term investigation with larger patient cohorts and further randomized trials are essential to verify the efficacy of the approach.
NIMG-56. PHENOTYPIC ANALYSIS OF RADIO-PATHOMIC MAPS IN DE-NOVO GLIOBLASTOMA IDENTIFIES DIFFERENCES IN BEVACIZUMAB TREATMENT RESPONSE
Authors: Samuel Bobholz, Allison Lowman, Savannah Duenweg, Aleksandra Winiarz, Fitzgerald Kyereme, Elizabeth Cochran, Jennifer Connelly, Wade Mueller, Mohit Agarwal, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Bevacizumab (Bev) treatment for recurrent glioblastoma ceases tumor angiogenesis, which changes tumor appearance on Gd enhanced T1-weighted imaging. However, little is known about how non-angiogenic portions of tumor are affected by Bev. Therefore, this study tested the hypothesis that patients with specific tumor appearance phenotypes outside contrast enhancement, as identified using autopsy tissue-based radio-pathomic maps, would show differences in survival benefit from Bev treatment. METHODS Previously published methods were used to create machine learning models that generate whole-brain maps of cellularity (Cell), extracellular fluid (ECF) and cytoplasm (Cyt) using glioma autopsy tissue aligned to the patient’s last MRI as ground truth (Bobholz et al. 2022). These maps were then generated for an independent dataset of glioblastoma patients (n=80) using baseline imaging acquired prior to treatment. Patients were then graded for qualitative characteristics of the non-enhancing margin, with phenotypes including Well-Circumscribed (WC) patients with no abnormal tissue surrounding the core, Hypercellular Front (HF) patients with areas of hypercellularity extending from the core, Necrotic Front (NF) patients with areas of necrosis extending from the core, and Hybrid Front (HYF) patients with both hypercellular and necrotic presence beyond the enhancing region. Kaplan Meier analysis was then used to compare survival outcomes between patients who did and did not receive Bev treatment within each phenotype to assess differences in treatment efficacy. RESULTS Only patients with NF or HYF showed significant survival increase with bevacizumab treatment (HR=2.35, p=0.02; and HR=2.45, p=0.03, respectively), with no significant or trending difference in survival observed for WC and HF patients. CONCLUSION Radio-pathomic phenotypes identify patients who show the greatest survival benefit from Bev treatment, which could be used to direct clinical decision-making.
CSIG-02. FOSL1 PROMOTES GLIOMA STEM CELLS TRAITS THROUGH INTERACTING WITH ITS BINDING PROTEIN PHOSPHORYLATED STAT3
Authors: Shanchun Go, Pendelton King, Mingli Liu
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioma stem cells (GSCs) have key roles in tumorigenesis, progression, and resistance to conventional treatments for glioblastoma. We reported that TRPM7 channels, which fused with C-terminal kinase, endow glioma cells with stem cell-like capacities of self-renewal. Here, we investigated the role of TRPM7 downstream target gene FOSL1’s post transcription in glioma stemness. METHODS 1) The immunohistochemical staining for FOSL1 was performed using the rabbit polyclonal anti-FOSL1 antibody in glioma tissue arrays from 76 Chinese patients and 10 normal individuals. The staining intensity of cells in TMA was evaluated in three different fields (≥100 cells/field). The semi-quantitative HSCORE was calculated for FOSL1. 2) Upon suppression of FOSL1 by siRNA FOSL1, GSC markers, CD133 expression was evaluated by flow cytometry using PE anti-human CD133 antibody, while ALDH1 enzymatic activity was assessed using an Aldefluor kit, in A172 and U87MG glioma cell lines and patient-derived xenoline PDX-L14 of proneural subtype. 3) To assay FOSL1 gene promoter activity, the 5’-flanking region of the human FOSL1 gene (1201bp) was inserted into the firefly luciferase reporter vector pGL3-Basic between MluI and BglII sites. For mutant construct, STAT3 binding sites were mutated using Q5 site-directed mutagenesis kit. RESULTS 1) Quantification of the IHC results showed that FOSL1’s positive nuclear staining was significantly higher in GBM (n=13, p=0.0005), grade III (n=12, p=0.0116), and grade II astrocytoma (n=51, p=0.0485) compared to that of normal brain tissue (n=10). 2) GSC markers CD133 and ALDH1 were positively associated with FOSL1 in glioma. 3) Phosphorylated STAT3 directly binds to the FOSL1 promoter and the activation levels of STAT3 have a positive effect on the transcriptional activity of FOSL1. CONCLUSION Our results demonstrated the role of TRPM7-regulated STAT3 activation directly regulated FOSL1 gene transcription, which shed new light on TRPM7/FOSL1-directed therapeutics in glioma. (This study was supported by NIH NIGMS GM121230)
INNV-10. OVERCOMING CHALLENGES AND OPTIMIZING PATIENT OUTCOMES WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: P Gage Gwyn, Peggy Frongillo, Anne Thomas, Nichelle Renae Adams
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Tumor Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, locoregional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM), recurrent GBM, and malignant pleural mesothelioma, and is being investigated in a range of solid tumors. METHODS Healthcare professionals (HCPs) specializing in radiation oncology, neuro-oncology, and medical oncology as well as patients with GBM and caregivers were asked to complete online surveys between October–December 2021 (HCPs) and July–September 2021 (patients/caregivers). RESULTS Overall, n=130 HCPs and n=50 patients/caregivers responded to the surveys. The majority (68%) of HCPs considered TTFields therapy + temozolomide a standard of care for ndGBM, yet only 35% of HCPs report strongly recommending it as a treatment option. Barriers to recommendation of TTFields therapy included the need for additional patient services and practice support with training, prescription process etc., and guidance on insurance coverage (31% for each), the need to increase patient awareness (20%), and lack of patient testimonials (20%). HCP perceptions of patient barriers were often higher than reported by patients themselves; time wearing device (46% vs 35%); treatment visibility (37% vs 24%), concerns with shaving head (37% vs 18%), and concerns with carrying device (34% vs 18%). Awareness of resources provided by the device manufacturer was relatively low (HCP: peer-peer knowledge exchange program [25%], TTFields therapy product brochures [16%–30%]; patient: webcasts [15%], patient website [23%], educational videos [25%–26%], educational brochures [26%–27%], buddy program [29%], and dedicated support service information [32%]), despite the desire for support. CONCLUSION Increasing awareness of existing HCP and patient support programs and resources continues to be critical in overcoming barriers to TTFields therapy initiation to optimize patient outcomes.
CNSC-05. ELECTROPHYSIOLOGICAL PATTERNS OF GLIOMA-INDUCED NEURONAL NETWORK REMODELING ARE CONSERVED ACROSS TUMOR SUBTYPE
Authors: Alexander Aabedi, Benjamin Lipkin, Jacob S Young, Leighton Hinkley, Anne Findlay, Andy Daniel, Saritha Krishna, Gray Umbach, Jasleen Kaur, Mitchel S Berger, Annette Molinaro, David Brang, Srikantan Nagarajan, Shawn L Hervey-Jumper
Journal: Neuro-Oncology (2022)

Abstract Recent evidence indicates that diffuse gliomas engage with neurons at the single-unit and circuit level through differing mechanisms. Certain malignant gliomas form glioma-neuron excitatory glutamatergic synapses and modulate neuron-neuron synapses through activity-dependent paracrine signaling, while others establish glioma-glioma connections via tumor microtubes. It is therefore possible that diffuse gliomas remodel neuronal circuits in a defined and predictable manner and demonstrate distinct electrophysiological profiles with prognostic and therapeutic significance. Here we apply machine learning principles in 140 patients across glioma subtypes to uncover unique electrophysiological features non-invasively via magnetoencephalography (discovery dataset) followed by feature validation using subdural electrocorticography (validation dataset). Following spatial-temporal registration, we fit an elastic net logistic regression classifier to distinguish between power spectra arising from glioma-remodeled cortex and within-subject control conditions. Model significance was determined non-parametrically by re-training each model 1,000 times with randomly permuted class labels and testing the true phi coefficient against the null distribution. In the discovery dataset, we were able to classify glioma infiltration based on tumor intrinsic neuronal activity (p &amp;lt; 0.05) in 127 patients (90.7%). We identified 30 electrophysiological features which revealed increased power in the delta range (1-4 Hz) and decreased power in the beta range (12-20 Hz) as a unique signature of glioma remodeling (p &amp;lt; 0.05) which was preserved in the validation dataset as well as across WHO 2021 diffuse glioma subtypes. In order to identify gene expression programs and signaling mechanisms that may contribute to glioma-induced remodeling but are potentially not identified in the current clinical classification scheme, we assessed targeted, next generation sequencing and DNA mutations as covariates, which again demonstrated the significance of the delta-beta spectral features. These data support converging mechanisms of glioma-induced neuronal network remodeling across tumor subtypes, setting the stage for novel therapies such as neuromodulation.
CTIM-21. NRG-BN010: A SAFETY RUN-IN AND PHASE II STUDY EVALUATING THE COMBINATION OF TOCILIZUMAB, ATEZOLIZUMAB, AND FRACTIONATED STEREOTACTIC RADIOTHERAPY IN RECURRENT GLIOBLASTOMA – TRIAL IN PROGRESS
Authors: Stephen Bagley, Mei-Yin Polley, Rupesh Kotecha, Steven Brem, Ranjini Tolakanahalli, Fabio Iwamoto, Mark Gilbert, Minhee Won, Minesh Mehta
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The glioblastoma (GBM) tumor microenvironment (TME) is characterized by a paucity of effector T cells and massive infiltration of immunosuppressive tumor-associated macrophages (TAMs). Inhibition of the interleukin-6 receptor (IL6R) has been demonstrated in preclinical models to repolarize TAMs toward an immunostimulatory phenotype, rendering GBM more susceptible to PD-1/PD-L1 inhibition. Additional preclinical data suggest that fractionated stereotactic radiotherapy (FSRT) can stimulate the release and presentation of tumor-specific antigens, acting as an in-situ vaccine and potentially converting a “cold” TME to a T cell-inflamed state. We designed a safety run-in and phase II study to evaluate the efficacy, safety, and impact on the TME of the combination of IL6R inhibition (tocilizumab), PD-L1 inhibition (atezolizumab), and FSRT in patients with recurrent GBM (rGBM). METHODS NRG-BN010 (NCT04729959) is open to enrollment for adults with rGBM following prior radiotherapy and has 3 components: a safety run-in to determine the recommended phase II dose (RP2D) of the treatment regimen, a phase II single-arm nonsurgical cohort to assess efficacy of the treatment regimen at the RP2D, and a window-of-opportunity surgical cohort. Once the safety run-in (n=12, 3 + 3 design) has determined the RP2D, the phase II and surgical cohorts will open. Phase II patients (n=25, Simon 2-stage design, primary endpoint objective radiographic response) receive an initial pre-FSRT cycle of tocilizumab (plus atezolizumab if included in the RP2D). Within 3-7 days later, the patient receives FSRT (8 Gy x 3 fx), followed by resumption of systemic therapy. Surgical cohort patients (n=16, 1:1 randomization) receive a neoadjuvant cycle of atezolizumab with (n=8) vs. without (n=8) tocilizumab, then FSRT 3-7 days later, then surgical resection 7-14 days after FSRT. Post-operatively, all patients resume systemic therapy at the RP2D. Fresh tumor tissues will be subjected to deep immune profiling to understand the impact of tocilizumab on TAMs in the GBM TME.
BIOM-20. IDENTIFICATION OF BLOOD BIOMARKERS FOR DIFFERENTIATING PSEUDOPROGRESSION FROM RECURRENCE IN GLIOBLASTOMA
Authors: Mitsutoshi Nakada, Sumio Ohtsuki, Yasuo Uchida, Riho Nakajima, Hemragul Sabit, Sho Tamai, Toshiya Ichinose, Masashi Kinoshita
Journal: Neuro-Oncology (2022)

Abstract After the initial treatment of glioblastoma, we occasionally encounter difficulty in distinguishing between pseudoprogression and recurrence. Observation without obtaining a pathological diagnosis is a common strategy in clinical practice. If the differentiation can be achieved easily, and reliably, early treatment can be introduced appropriately, leading to the benefits of early glioblastoma treatment. In this study, we attempted to identify blood biomarkers that help distinguish between recurrence and pseudoprogression. Blood samples were collected in 25 cases of primary glioblastoma, IDH wild type, at three time points: before treatment, after standard treatment: operation and temozolomide chemotherapy with concomitant radiation therapy, and when an enhancing lesion was recognized (21 cases of recurrence, 4 cases of pseudoprogression). Gelsolin (GSN), Apolipoprotein A-IV, Osteopontin, SERPINA3, ITIH2/4 Ceruloplasmin, LRG1, Collagen-1A2, which we previously extracted as diagnostic markers, using the comprehensive proteomics SWATH method, in blood samples of healthy volunteers and patients with glioblastoma (PLoS One. 2018, J Proteome Res. 2020), were analyzed. Absolute quantitative values of candidate molecules in the blood were obtained using a commercially available enzyme-linked immunoassay. Among the candidate molecules, GSN was significantly lower in pseudoprogression than in recurrence (p = 0.0032), and ROC analysis showed sensitivity of 95%, specificity of 100%, and an AUC = 0.98, which makes GSN a useful molecule to consider as a differential marker. We previously reported that GSN, actin binding protein, and inflammation markers are downregulated in glioblastoma (Cancer Sci. 2020). In summary, GSN was extracted as a candidate blood biomarker for the diagnosis of pseudoprogression. We are planning to validate the research with nationwide multi-institutional studies.